Transfer of IL-1Ra cDNA to the synovial linings of joints has shown both safety and efficacy in animal models of rheumatoid- and osteo-arthritis. A phase I study is proposed to assess applicability of local, in vivo gene transfer to joints with osteoarthritis, an excellent candidate for this type of gene therapy. In this protocol IL-1Ra cDNA will be delivered by in vivo gene transfer to the knee joints of 9 subjects with osteoarthritis of the knee. A recombinant, serotype 2, adeno-associated virus (AAV.IL-1Ra) will be used for this purpose, with transgene expression driven by the human cytomegalovirus immediate-early promoter. Clinical grade AAV.IL-1Ra will be produced by the National Gene Vector Laboratory. In a dose-escalation manner, 3 subjects will each receive 5x1011 (low dose), 5x1012 (middle dose) or 5x1013 (high dose) viral particles in one knee joint, twelve weeks before total knee joint replacement surgery. Synovial fluid will be aspirated from the knee joints, and peripheral blood withdrawn, immediately before injection of the virus, and again immediately before joint replacement surgery. Intraarticular transgene expression will be assessed by measuring the IL- 1Ra concentration of the synovial fluid. IL-1Ra concentrations in peripheral blood will also be measured. Articular tissues recovered at the time of joint replacement surgery will be examined for the presence of integrated and episomal viral genomes, and for transgene expression. Possible adverse intraarticular events will be evaluated by MR imaging of joints immediately before viral delivery and immediately before joint replacement surgery. Additional safety information will be gathered by analysis of peripheral blood samples drawn immediately before injection of virus, immediately before joint replacement surgery, and 3, 6 and 12 months after joint replacement surgery. If this protocol is able to generate relevant levels of intraarticular IL-1Ra transgene expression in a safe and efficient manner, it will set the stage for a subsequent interventional study to determine efficacy in osteoarthritis.